68 The confounder in time of confusion: a case report on Multisystem Inflammatory Syndrome in Children (MIS-C)

Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a novel, life-threatening gghyperinflammatory condition that develops in children about 2–6 weeks1 after infection with SARSCoV2. It can create a diagnostic challenge especially if there is no clear history of prior COVID-19 infection or exposure, and because of the varying range of phenotypes and severity. The prognosis however is good as only a 5% mortality has been reported thus far. Methods-Case report Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. 2020; 383(4):334–46. Case description A 1 year 7-month-old African male presented with persistent fever, vomiting, diarrhoea and poor feeding for 6 days with irritability for 1 day prior to admission. The fever peaked at 40.2C. He had no cough, runny nose or difficulty in breathing. Five days prior to onset of the above symptoms, he was on outpatient treatment for acute tonsillitis and otitis media post exposure to SARS-CoV-2 from the older sibling. On examination he was noted to have oral thrush. 68 Table 1 Summary of initial investigations WBC (x109/L) ANC (x109/L) HB (g/dL) MCV (fl) Platelets (103/µL) BUN (mmol/L) HCO3 (mmol/L) Na (mmol/L) K (mmol/L) CRP (mg/l) 18.8 11.97 8.3 79 146 15.5 16.9 137 3.49 139 Stool M/C/S: Campylobacter positive Vitamin D: 16.9. He was admitted to the general paediatric ward and was started intravenous fluids, azithromycin, ceftriaxone, paracetamol, ibuprofen and nystatin. Two days after admission, he was noted to be in fluid refractory shock, that needed inotropic support. He was transferred to Paediatric High Dependency Unit and received Intravenous fluids, oxygen via nasal prongs and transfused with packed red blood cells. On day 3 of admission, he was noted to have red swollen cracked lips, exfoliation of skin, swollen feet with a vasculitic rash and a strawberry tongue. A diagnosis of Kawasaki disease with a differential of multisystem inflammatory syndrome was then made. Further investigations were done An ECHO was done that showed moderate cardiac dysfunction, with an Ejection Fraction of 51%, dilated chambers, and mild tricuspid and mitral valve regurgitation which was in support of MIS-C according to the CDC case definition. The child was started on IV immunoglobulin, and subsequent resolution of fevers and hypotension ensued. Three days later, he was noted to have recurrence of fevers and tachypnoea, with persistence of the swelling of the extremities. He received a 2nd dose of IV immunoglobulin and aspirin. Antibiotics were changed to Meropenem, Vancomycin and Fluconazole. His respiratory status worsened, with increased oxygen demand. A chest X-Ray done showed features of pneumonia and a right sided pleural effusion. He was then transferred to ICU. A thoracocentesis was with drainage of 45mls of yellowish blood-stained fluid, with a mixed picture when subjected to Light’s Criteria. At this point, the results from a COVID-19 IgG came back positive, clarifying the diagnosis to be MIS-C. Incidentally, was noted to have hypocalcaemia with low Vitamin D levels. The patient improved with resolution of shock and the pleural effusions, and was discharged home after 13 days in hospital, on Aspirin, Prednisone, Omeprazole, Calcimax, Aldactone and Furosemide. He was reviewed as an outpatient 12 days later, and he was clinically stable. A repeat ECHO was done which showed a structurally normal heart with an EF of 70%. He was advised to taper off steroids, stop furosemide and continue aspirin. A subsequent review 1 month later, showed that he was doing well. Aspirin was discontinued and he was discharged from the cardiac clinic. He was to be reviewed again in the rheumatology clinic after 4 months. Discussion Our patient’s initial presentation was a confounder as it presented as acute gastroenteritis. His clinical picture evolved to present with features that fulfilled the criteria for Kawasaki disease and the case definitions for Multisystem Inflammatory Syndrome in Children (MIS-C)1–3. The initial presentation of gastrointestinal symptoms pointed towards a diagnosis of MIS-C, where gastrointestinal symptoms present in > 80% patients, with some presenting with acute surgical abdomen. His illness progressed rapidly to the point of requiring critical care due to haemodynamic instability, severe cardiac dysfunction and multi-organ involvement (renal, pulmonary, haematological). This is not in keeping with Kawasaki disease, in which <5% of patients develop Kawasaki Disease Shock Syndrome (KDSS) need ICU management. 1The child was also noted to have low vitamin D levels. This raises the possibility of a relationship between MIS-C and low vitamin D levels, as Vitamin D is known to be involved in immune modulation.1,4 Conclusion A high index of suspicion of MIS-C is required in children with COVID exposure with otherwise typical presentation of common paediatric emergency ailments. Although the management is symptom-driven, early recognition and institution of management for MIS-C could be important in delaying or avoiding complications. Further studies would be needed to better understand the aetiology of this disease, as well as the disease course, and hence if timely management contributes to a better clinical outcome for our patients. CDC (2020) Multisystem Inflammatory Syndrome in Children (MIS-C) [Internet]. Centers for Disease Control and Prevention. 1 Multisystem inflammatory syndrome in children and adolescents with COVID-19 (2020) Scientific brief: World Health Organisation. 2Royal College of Paediatrics and Child Health (2020) Guidance—Pediatric multisystem inflammatory syndrome temporally associated with COVID-19, 2020. 3Kabeerdoss J, Pilania RK, Karkhele R, Kumar TS, Danda D, Singh S. Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management. Rheumatol Int. 2021; 41(1):19–32 4Yılmaz, K., & Şen, V. (2020). Is vitamin D deficiency a risk factor for COVID-19 in children? Pediatric pulmonology, 55(12), 3595–3601. https://doi.org/10.1002/ppul.25106


Background
Vitamin D prevents deficiency rickets, but its prescription must be weighed carefully! Objective We report a rare case of iatrogenic toxic hypervitaminosis D in a child with vitamin D resistant rickets. . .! Methods We admitted a two-year-old girl, presenting signs of rickets resistant to the usual then therapeutic doses of vitamin D3. Vitamin D2 in oral suspension is then ordered in addition, for a few weeks until the onset of hearing loss motivating her hospitalization in pediatrics.

Results
Biological and radiological explorations revealed renal failure with threatening arterial hypertension, as well as diffuse and severe arteriosclerosis on Doppler signal. Eviction (stopping vitamin D in all its forms), symptomatic and conservative management by (converting-enzyme inhibitors) and hydration allowed a progressive blood pressure normalisation, arteriosclerosis disappearance (undetected by Doppler signal and by angio-scan) along with a gradual normalising of the kidney function; all this over a period of 2 years The girl actually had hypophosphatemic rickets, and oral phosphorus (syrup) was also prescribed Conclusion Vitamin D is potentially toxic with sometimes severe renal risks (lithiasis, nephrocalcinosis), and hypercalcemia might be severe, especially if renal function is impaired. Blindly treating any rickets with vitamin D can be adventurous and might expose the child to serious morbidity.

Case description
A 1 year 7-month-old African male presented with persistent fever, vomiting, diarrhoea and poor feeding for 6 days with irritability for 1 day prior to admission. The fever peaked at 40.2C. He had no cough, runny nose or difficulty in breathing. Five days prior to onset of the above symptoms, he was on outpatient treatment for acute tonsillitis and otitis media post exposure to SARS-CoV-2 from the older sibling. On examination he was noted to have oral thrush. 68  He was admitted to the general paediatric ward and was started intravenous fluids, azithromycin, ceftriaxone, paracetamol, ibuprofen and nystatin. Two days after admission, he was noted to be in fluid refractory shock, that needed inotropic support. He was transferred to Paediatric High Dependency Unit and received Intravenous fluids, oxygen via nasal prongs and transfused with packed red blood cells.
On day 3 of admission, he was noted to have red swollen cracked lips, exfoliation of skin, swollen feet with a vasculitic rash and a strawberry tongue. A diagnosis of Kawasaki disease with a differential of multisystem inflammatory syndrome was then made. Further investigations were done An ECHO was done that showed moderate cardiac dysfunction, with an Ejection Fraction of 51%, dilated chambers, and mild tricuspid and mitral valve regurgitation which was in support of MIS-C according to the CDC case definition. The child was started on IV immunoglobulin, and subsequent resolution of fevers and hypotension ensued. Three days later, he was noted to have recurrence of fevers and tachypnoea, with persistence of the swelling of the extremities. He received a 2 nd dose of IV immunoglobulin and aspirin. Antibiotics were changed to Meropenem, Vancomycin and Fluconazole. His respiratory status worsened, with increased oxygen demand. A chest X-Ray done showed features of pneumonia and a right sided pleural effusion. He was then transferred to ICU. A thoracocentesis was with drainage of 45mls of yellowish blood-stained fluid, with a mixed picture when subjected to Light's Criteria. At this point, the results from a COVID-19 IgG came back positive, clarifying the diagnosis to be MIS-C. Incidentally, was noted to have hypocalcaemia with low Vitamin D levels.
The patient improved with resolution of shock and the pleural effusions, and was discharged home after 13 days in hospital, on Aspirin, Prednisone, Omeprazole, Calcimax, Aldactone and Furosemide.
He was reviewed as an outpatient 12 days later, and he was clinically stable. A repeat ECHO was done which showed a structurally normal heart with an EF of 70%. He was advised to taper off steroids, stop furosemide and continue aspirin. A subsequent review 1 month later, showed that he was doing well. Aspirin was discontinued and he was discharged from the cardiac clinic. He was to be reviewed again in the rheumatology clinic after 4 months.

Discussion
Our patient's initial presentation was a confounder as it presented as acute gastroenteritis. His clinical picture evolved to present with features that fulfilled the criteria for Kawasaki disease and the case definitions for Multisystem Inflammatory Syndrome in Children (MIS-C) 1-3 . The initial presentation of gastrointestinal symptoms pointed towards a diagnosis of MIS-C, where gastrointestinal symptoms present in > 80% patients, with some presenting with acute surgical abdomen. His illness progressed rapidly to the point of requiring critical care due to haemodynamic instability, severe cardiac dysfunction and multi-organ involvement (renal, pulmonary, haematological). This is not in keeping with Kawasaki disease, in which <5% of patients develop Kawasaki Disease Shock Syndrome (KDSS) need ICU management. 1 The child was also noted to have low vitamin D levels. This raises the possibility of a relationship between MIS-C and low vitamin D levels, as Vitamin D is known to be involved in immune modulation. His uncle had a COVID-19 infection 6 months ago and they stayed in the same house during the infection. On physical examination, respiratory sounds were less audible in the left lung baseline. The blood pressure was measured 128/71 mmHg in the right arm, 122/72 mmHg in the left arm, 106/67 mmHg in the right leg, and 107/74 mmHg in the left leg. Peripheral pulses were weaker in the lower extremities than in the upper extremities. High acute phase reactants and anaemia were detected in the laboratory. (Table 1) Anti-ds DNA was positive, and anti-neutrophil cytoplasmic antibody (cANCA) was negative. Infection screening was negative.
In thorax and abdomen computed tomography (CT), 20 mm pericardium and 10 mm pleural effusion and mural thickening along the aorta of 20-25 cm from the descending thoracic aorta to the suprarenal level in the proximal 2 cm of the left subclavian artery and mild narrowing of the celiac and superior mesenteric artery orifices were detected. The patient was diagnosed with TA. She was treated with intravenous 30 mg/kg/day methylprednisolone for 3 days. The patient was discharged with oral prednisolone, methotrexate, and anti-TNF therapy.

Case 2
A 17-year-old female patient was admitted to our center with complaints of back pain for 2 months, dry cough, weight loss (3 kg in 2 months), and fever for 2 days. It was learned that the patient had a COVID-19 infection 5 months ago. On physical examination, blood pressure was measured 94/59 mmHg in the left arm, 103/60 mmHg in the right arm, 125/77 mmHg in the left leg, and 132/80 mmHg in the right leg. Peripheral pulses were weaker in the lower extremities compared with the upper ones. There was a 1/6 systolic murmur in the aortic focus. Other system examination was normal. Laboratory tests revealed elevated acute phase reactants, thrombocytosis, and anaemia. (Table 1) Positron emission tomography-CT (PET-CT) revealed increased FDG uptake in both common carotid, aortic arch, ascending and descending aortic walls. In MR angiography, localized enlargement and stenosis of the aortic arch, wide ascending aorta, stenosis in the left subclavian artery, and the origin level of the left renal artery, and then a slight enlargement was observed. Based on the present findings, the patient was diagnosed with TA. Infection screening was negative. The patient was given 30 mg/kg/day intravenous methylprednisolone for 3 days and continued with oral prednisolone, methotrexate, and etanercept.

Discussion
Timely diagnosis and treatment in TA is very important in preventing irreversible vascular damage resulting in ischaemia of vital organs. It should be kept in mind that TA and other vasculitides may occur after COVID-19 infection.

Background
Kawasaki disease (kDa) is a multisystemic vasculitis affecting medium and small vessels with a predilection for the coronary arteries. It appears to be very similar to the pediatric multisystemic inflammatory syndrome (PIMS), which is a post-infectious inflammatory condition occurring after SARS-COV2 infection. Although these two entities have clinical and biological similarities, marked differences are identified. The aim of this study is to compare the two conditions in order to highlight the specific criteria of each of these related entities and to describe their demographic, clinical, biological and therapeutic characteristics in our context.

Background
Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after SARS-CoV-2 infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide.

Methods
A cohort of children with MIS-C and healthy children was recruited from May 2020 to May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed.